Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease

Yao, Yuan; Huo, Tong; Lin, Yi-Lun; Nie, Shenyou; Wu, Fangrui; Hua, Yuanda; Wu, Jingyu; Kneubehl, Alexander R.; Vogt, Megan B.; Rico-Hesse, Rebecca; Song, Yongcheng

doi:10.1021/jacs.9b02505

Title: Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease

Journal Article · Tue Apr 23 00:00:00 EDT 2019 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.9b02505· OSTI ID:1561316

Yao, Yuan ^[1]; Huo, Tong ^[1]; Lin, Yi-Lun ^[1]; Nie, Shenyou ^[1]; Wu, Fangrui ^[1]; Hua, Yuanda ^[1]; Wu, Jingyu ^[1]; Kneubehl, Alexander R. ^[1]; Vogt, Megan B. ^[1]; Rico-Hesse, Rebecca ^[1];

^[1]

Baylor College of Medicine, Houston, TX (United States)

Flaviviruses, including dengue, West Nile and recently emerged Zika virus, are important human pathogens, but there are no drugs to prevent or treat these viral infections. The highly conserved Flavivirus NS2B-NS3 protease is essential for viral replication and therefore a drug target. Compound screening followed by medicinal chemistry yielded a series of drug-like, broadly active inhibitors of Flavivirus proteases with IC₅₀ as low as 120 nM. The inhibitor exhibited significant antiviral activities in cells (EC₆₈: 300–600 nM) and in a mouse model of Zika virus infection. X-ray studies reveal that the inhibitors bind to an allosteric, mostly hydrophobic pocket of dengue NS3 and hold the protease in an open, catalytically inactive conformation. Finally, the inhibitors and their binding structures would be useful for rational drug development targeting Zika, dengue and other Flaviviruses.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States).Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; USDOD; National Institutes of Health (NIH)

Grant/Contract Number:: W81XWH-18-1-0368; RP150129; RP180177; R01AI099483; R01AI098715

OSTI ID:: 1561316

Journal Information:: Journal of the American Chemical Society, Vol. 141, Issue 17; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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flavivirus NS2B-NS3 protease
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Title: Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease

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